This invention relates to 3-hydroxyazabenzothiophenes having the 2-position substituted with an optionally substituted aryl, aralkyl, alkyl, or alkenyl group, for example, 3-acetyloxy-7-aza-2-phenyl-benzo[b]thiophene.
These novel azabenzothiophenes are found to be either specific 5-lipoxygenase inhibitors or dual 5-lipoxygenase/cyclooxygenase inhibitors and are therefore useful in the treatment of prostaglandin and/or leukotriene mediated diseases.
Among various potent biological mediators derived from the oxygenation of arachidonic acid, prostaglandins and leukotrienes have been linked to various diseases. Notably, the biosynthesis of prostaglandins has been identified as a cause of inflammation, arthritic conditions and pain, and the formation of leukotrienes has been connected to immediate hypersensitivity reactions and pro-inflammatory effects. It has been established that arachidonic acid undergoes oxygenation via two major enzymatic pathways:
(1) The pathway catalyzed by the enzyme cyclooxygenase; and PA1 (2) The pathway catalyzed by the enzyme 5-lipoxygenase. PA1 (1) Q, where Q is H; loweralkyl, especially C.sub.1-6 alkyl; haloloweralkyl, especially fluoro or chloro C.sub.1-6 alkyl such as trifluoromethyl; phenyl of formula ##STR2## or naphthyl; or imidazole of formula ##STR3## wherein R.sup.3 is H, C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.3-6 cycloalkyl or halo C.sub.1-6 alkyl; PA1 (2) halo, especially chloro, fluoro, or bromo; PA1 (3) loweralkenyl, especially C.sub.2-6 alkenyl, such as ethenyl and allyl; PA1 (4) loweralkynyl, especially C.sub.2-6 alkynyl, for example, ethynyl or n-butynyl; PA1 (5) ##STR4## wherein q is an integer of 0 to 2; (6) --OQ; PA1 (7) --CHQCOQ.sup.1, where Q.sup.1 is Q and can be the same as or different from Q; PA1 (8) --CHQ(CO)OQ.sup.1 ; PA1 (9) --CH.sub.2 SQ or --CHQSQ.sup.1 ; PA1 (10) --CH.sub.2 OQ or --CHQOQ.sup.1 ; PA1 (11) --COQ; PA1 (12) --(CO)OQ; PA1 (13) --O(CO)Q; PA1 (14) --NQQ.sup.1 ; PA1 (15) --NQ(CO)Q.sup.1 ; PA1 (16) --NQSO.sub.2 Q.sup.1 ; PA1 (17) --SO.sub.2 NQQ.sup.1 ; PA1 (18) --SO.sub.3 Q PA1 (19) --CN; PA1 (20) --NO.sub.2 ; PA1 (21) --CONQQ.sup.1 ; PA1 (22) --NO; PA1 (23) --CSQ.sup.1 ; PA1 (24) --CSNQQ ; PA1 (25) --CF.sub.2 SQ; PA1 (26) --CF.sub.2 O Q; PA1 (27) --NQCONHQ.sup.1 or --NQCONQ.sup.1 Q.sup.2 ; or PA1 (28) -methylenedioxy; PA1 (a) H; PA1 (b) loweralkyl, especially C.sub.1-6 alkyl, such as methyl, ethyl, i-propyl, n-propyl, t-butyl, n-butyl, i-pentyl, n-pentyl, and n-hexyl; PA1 (e) haloloweralkyl, especially halo C.sub.1-6 alkyl, e.g. --CF.sub.3, --CHF.sub.2, --CF.sub.2 CF.sub.3 ; PA1 (f) heteroaryl or heteroaryl substituted with X.sub.1 and X.sub.2 especially pyridyl, imidazolyl, pyrryl, furyl or thienyl wherein X.sub.1 and X.sub.2 are as previously defined; PA1 (g) benzyl of formula ##STR6## (h) loweralkynyl, especially C.sub.1-6 alkynyl, such as HC.tbd.C--; CH.sub.3 --C.tbd.C--, or HC.tbd.C--CH.sub.2 --; PA1 (i) loweralkenyl, especially C.sub.1-6 alkenyl, such as CH.sub.2 .dbd.CH--, CH.sub.3 CH.dbd.CH--, CH.sub.2 .dbd.CHCH.sub.2 --, CH.sub.3 CH.dbd.CH--CH.sub.2 --, (CH.sub.3).sub.2 C.dbd.CH-- or --CH.dbd.CHCOOR.sup.2 wherein R.sup.2 is loweralkyl, especially C.sub.1-6 alkyl, PA1 (j) aralkenyl of formula ##STR7## wherein Y.sub.1 and Y.sub.2 independently are phenyl and heteroaryl as previously defined; PA1 (k) aralkynyl of formula EQU --C.tbd.C--Y.sub.1 PA1 (1) (CH.sub.2).sub.m (CO)R.sup.3 wherein m is an integer of C.sub.1-6 and R.sup.3 is H, C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.3-6 cycloalkyl or haloC.sub.1-6 alkyl; PA1 (m) --(CH.sub.2).sub.m OR.sup.3 ; PA1 (n) --(CH.sub.2).sub.m O(CO)OR.sup.3 ; PA1 (o) --(CH.sub.2).sub.m NR.sup.3 R.sup.4 wherein R.sup.4 can be the same or different from R.sup.3 and R.sup.4 is R.sup.3 ; PA1 (p) --(CH.sub.2).sub.m --NR.sup.3 (CO)R.sup.4 ; PA1 (q) --(CH.sub.2).sub.m (CO)OR.sup.3 ; or ##STR8## R is (a) H; PA1 (b) --(CO)R.sup.3 ; PA1 (c) --(CO)OR.sup.3 ; PA1 (d) --(CO)NR.sup.3 R.sup.4 ; PA1 (e) --(CO)SR.sup.3 ; PA1 (f) --(CH.sub.2).sub.m COR.sup.3 ; PA1 (g) --(CH.sub.2).sub.m OR.sup.3 ; PA1 (h) --(CH.sub.2).sub.m O(CO)OR.sup.3 ; PA1 (i) --(CH.sub.2).sub.m NR.sup.3 R.sup.4 ; PA1 (j) --(CH.sub.2).sub.m NR.sup.3 (CO)R.sup.4 ; PA1 (k) loweralkyl as previously defined; PA1 (l) lowercycloalkyl as previously defined; or PA1 (m) haloloweralkyl as previously defined; and PA1 0 or 1. PA1 (a) H; PA1 (b) C.sub.1-6 alkyl; PA1 (c) halo; PA1 (d) halo-C.sub.1-6 -alkyl, e.g. CF.sub.3 ; PA1 (e) CN; PA1 (f) --(CO)OR.sup.3 ; PA1 (g) --OC.sub.1-6 alkyl; PA1 (h) phenyl--CH(OH)--; PA1 (i) CH.sub.2 S-Aryl; or PA1 (j) --CH.sub.2 S--(CH.sub.2).sub.x -aryl; wherein x is 1 to 4; PA1 (a) H; PA1 (b) -methylenedioxy; PA1 (c) halo-C.sub.1-6 alkyl, e.g., CF.sub.3 ; PA1 (d) halo; PA1 (e) CN; PA1 (f) --OC.sub.1-6 alkyl; PA1 (g) --OC.sub.1-6 alkylphenyl; PA1 (h) --(CO)OR.sup.3 ; PA1 (i) C.sub.1-6 alkyl; or PA1 (g) NO.sub.2
Interruption of these pathways by enzyme inhibition has been explored for effective therapy. For example, non-steroidal anti-inflammatory drugs (NSAID's) such as aspirin, indomethacin and diflunisal are known cyclooxygenase inhibitors which inhibit the process wherein arachidonic acid is oxygenated via cyclooxygenase to prostaglandins and thromboxanes.
Recently, it has been observed that certain leukotrienes are responsible for diseases related to immediate hypersensitivity reactions such as human asthma, allergic disorders, and skin diseases. In addition, certain leukotrienes and derivatives thereof are believed to play an important role in causing inflammation (B. Samuelsson, Science, 220, 568 (1983); D. Bailey et al, Ann. Rpts. Med. Chem., 17, 203 (1982)).